(1) Field of the Invention
During the study of limonene as a hand cleaner, the applicants found that fully oxygenated limonene is a bactericide. A review of the literature revealed that oxygenated limonene contains several oxidation products including: cis and trans-carveol, trans-p-menth-8-ene-1,2-diol, limonene 1,2-epoxide, limonene 8,9-epoxide, cis and trans-p-mentha-2,8-dien-1-ol, and perillyl alcohol, as was outlined by Blumann in Chemical Abstracts, Volume 63, 1965, on page 1819. The applicants found that a principal bactericide generated by the oxidation of limonene is perillyl alcohol which, in bactericidal concentrations, kills bacteria and yeasts.
Perillyl alcohol is a monocyclic monoterpene similar to limonene. Limonene is not bactericidal. Their chemical formulas follow below. ##STR1##
It should be noted that the formula for perillyl alcohol is identical to the formula for limonene with the exception of a hydroxyl group which replaces a hydrogen atom at carbon 7. Because limonene is not bactericidal, the exchange of a hydroxyl group for a hydrogen atom at carbon 7, was not expected to make the resulting compound (perillyl alcohol) bactericidal. All other monocyclic monoterpenes terpenes that have known bactericidal activity are similar to limonene, but have a hydroxyl group or an oxygen atom replacing a hydrogen atom on the benzene ring at carbons 2, 3, 4 or 8 (as opposed carbon 7, 9, or 10) that is appreciated in the structures of: carveol, carvone, hydrocarveol, hydrocarvone, pulegone, isopulegol, menthol, menthone, terpinen-4-ol, and a-terpineol which follow. None of the monocyclic monoterpenes that have bactericidal activity have a hydroxyl group at the carbon 7, 9, or 10 position. ##STR2##
Although it was not expected, the applicants were totally surprised to find that perillyl alcohol is bactericidal to bacteria and yeasts.
Perillyl alcohol is an oil with a terpenic aroma. It is insoluble in water, is poorly soluble in propylene glycol, and is almost insoluble in glycerine. Perillyl alcohol is soluble in alcohol and is miscible in oil. It is used as a flavoring agent for cosmetics and perfumes, but heretofore, it has not been used as a bactericide. Perillyl alcohol can be produced by the oxidation of limonene as was demonstrated by Blumann in Chemical Abstracts, Volume 63, 1965 on page 1819, and Bardychev in Chemical Abstracts, Volume 80, 1974, page 359. It can be produced by the acetylation of limonene as described by Ansari, Hifzure R. (German Offen 2,513,910 and Canadian Patent No. 1,077,959). Walling made perillyl alcohol (Canadian Patent No. 981,695) from beta pinene by adding benzyl peroxide to beta pinene followed by alkaline hydrolysis to perillyl alcohol.
(2) Description of the Prior Art
Zukerman studies the effect of auto-oxidized d-limonene on bacteria, but found it was weakly bacteriostatic, was unstable, and lost its bacteriostatic effect on keeping as was discussed in Nature 169:517 (1951). He never studied perillyl alcohol. Kurita investigated the fungicidal activity of several components of essential oils as was reported in Biol. Chem., 45(4), 945-952, 1981, but he never studied the bactericidal activity of perillyl alcohol against bacteria nor yeasts. Murdock and Allen showed that the germicidal effect of sodium benzoate against yeasts was enhanced by the orange peel oil and d-limonene, as was outlined in Food Technology, Vol. 14, No. 9, 1960, pages 441-5. They never studied the antimicrobial activity of perillyl alcohol against bacteria nor yeasts. Kellner et al demonstrated that several ethereal oils and some of their constituents have antimicrobial activity as was reported in Arneimittel-Forschung, 5, 224-9, 1955. He confirmed that limonene is not bactericidal. He never studied perillyl alcohol for bactericidal activity. Gauvreau showed a means of producing disinfecting compositions in U.S. Pat. No. 3,595,975 by combining cetyl pyridinium hydrochloride with terpenes to form antiseptics, but he never studied the use of perillyl alcohol alone nor in combination with cetyl pyridinium hydrochloride. The active ingredient in his disinfecting compositions was cetyl pyridinium hydrochloride (and not the terpenes). A. Morel revealed the sterilizing action of carveol, dihydrocarveol, and their ozonization productions in Comp. Rend. Soc. Biol. Volume 115, pages 536-8 (1934). He never studied the bactericidal effect of perillyl alcohol.
It should be pointed out that drugs which are bactericidal are usually not fungicidal, and drugs which are fungicidal are usually not bactericidal In addition, drugs which are bactericidal frequently promote the growth of yeasts. Table A, which follows, exemplifies the bactericidal and fungicidal activity of several commonly used antibacterial, antiyeast, and antifungal antibiotics.
TABLE A ______________________________________ ANTIBIOTIC ACTIVITY AGAINST Gm + Gm - ANTIBIOTICS Bact Bact A F Bact Yeast Fungi ______________________________________ A. Anti-bacterial 1. Ampicillin Y Y N N N 2. Cephalothin Y Y N N N 3. Chloram- Y Y N N N phenicol 4. Erythromycin Y N N N N 5. Ethambutol N N Y N N 6. Gentamicin Y Y N N N 7. Isoniazid N N Y N N 8. Nitrofurantoin N Y N N N 9. Penicillin Y N N N N 10. Rifampin Y N Y N N 11. Streptomycin Y Y Y N N 12. Sulfonamides N Y N N N 13. Tetracycline Y Y N N N 14. Vancomycin Y Y N N N B. Anti-Fungal 1. Chlotrimazole N N N Y Y 2. Griseofulvin N N N N Y C. Anti-Yeast 1. Nystatin N N N Y N 2. Gentian Violet N N N Y N ______________________________________ Gm + Bact = Gram Positive Bacteria, Gm - Bact = Gram Negative Bacteria, F Bact = Acid Fast Bacteria, Y = Kills Organism, N = No Activity Against Organism
It should be noted in the table above that none of the antibacterial antibiotics kill fungi, and none of the antifungal nor anti-yeast antibiotics kill bacteria. Thus, an antifungal antibiotic is not expected to kill bacteria and a antibacterial antibiotic is not expected to kill fungi or yeasts. Antifungal antibiotics do not necessarily kill yeasts and anti-yeast antibiotics do not necessarily kill fungi.